Pregnane X receptor prevents hepatorenal toxicity from cholesterol metabolites.

Abstract	Efficient detoxification and clearance of cholesterol metabolites such as oxysterols, bile alcohols, and bile acids are critical for survival because they can promote liver and cardiovascular disease. We report here that loss of the nuclear xenobiotic receptor PXR (pregnane X receptor), a regulator of enterohepatic drug metabolism and clearance, results in an unexpected acute lethality associated with signs of severe hepatorenal failure when mice are fed with a diet that elicits accumulation of cholesterol and its metabolites. Induction of a distinct drug clearance program by a high-affinity ligand for the related nuclear receptor, the constitutive androstane receptor, does not overcome the lethality, indicating the unique requirement of PXR for detoxification. We propose that the PXR signaling pathway protects the body from toxic dietary cholesterol metabolites, and, by extension, PXR ligands may ameliorate human diseases such as cholestatic liver diseases and the associating acute renal failure.
Authors	Junichiro Sonoda, Ling Wa Chong, Michael Downes, Grant D Barish, Sally Coulter, Christopher Liddle, Chih-Hao Lee, Ronald M Evans
Journal	Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 102 Issue 6 Pg. 2198-203 (Feb 08 2005) ISSN: 0027-8424 [Print] United States
PMID	15671183 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Bile Acids and Salts Biomarkers Cholesterol, Dietary Constitutive Androstane Receptor Pregnane X Receptor Receptors, Cytoplasmic and Nuclear Receptors, Steroid Transcription Factors
Topics	Animals Bile Acids and Salts (blood) Biomarkers Cholesterol, Dietary (metabolism) Constitutive Androstane Receptor Gene Expression Profiling Hepatorenal Syndrome (metabolism, pathology) Humans Hyperbilirubinemia (blood) Male Mice Mice, Inbred C57BL Mice, Knockout Oligonucleotide Array Sequence Analysis Phenotype Pregnane X Receptor Receptors, Cytoplasmic and Nuclear (genetics, metabolism) Receptors, Steroid (genetics, metabolism) Signal Transduction (physiology) Survival Rate Transcription Factors (metabolism)

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